Saracatinib

SOUTH SAN FRANCISCO, Calif., June 30, 2026 (GLOBE NEWSWIRE) -- Quince Therapeutics, Inc. (Nasdaq: QNCX), a clinical stage biopharmaceutical company focused on the development of novel, disease modifying therapies for serious underserved diseases, today announced the formation of a Scientific Advisory Board (SAB) of leading clinicians to support the advancement of LAM-001, an inhaled formulation of rapamycin (mTOR inhibitor) designed to enhance pulmonary delivery and reduce systemic exposure. Comprised of internationally recognized experts in pulmonary medicine, the SAB will be instrumental in progressing the development of LAM-001 across multiple pulmonary indications including pulmonary hypertension associated with interstitial lung disease (PH-ILD), bronchiolitis obliterans syndrome post lung transplant (BOS), and sarcoidosis associated pulmonary hypertension (SAPH). “I am honored to serve as the Chairman of Quince’s Scientific Advisory Board to help guide the development of LAM-001 across a range of pulmonary conditions where evidence strongly suggests it has a direct effect on the underlying disease pathophysiology,” commented Paul Yu, M.D., Ph.D., Director, Cardiovascular Research Center, Massachusetts General Hospital. “On behalf of the SAB, we are encouraged by the clinically relevant improvement seen in measures of lung function in patients with functional class III pulmonary hypertension treated with LAM-001. With continued development, we believe LAM-001 has the potential to provide patients with a much needed treatment option that, importantly, may be utilized in conjunction with currently available therapies to achieve better health outcomes.” Scientific Advisory Board members: Paul Yu, M.D., Ph.D. (Chairman of SAB) Dr. Paul Yu is Director of the Cardiovascular Research Center at Massachusetts General Hospital and Associate Professor of Medicine at Harvard Medical School, where he holds the Charles and Elizabeth Sanders Endowed Chair. A physician-scientist trained in immunology and cardiovascular medicine, Dr. Yu’s research focuses on BMP and TGF-β signaling in cardiovascular homeostasis, repair, and disease. His work spans pulmonary vascular disease, cardiovascular rheumatology, and rare disorders such as fibrodysplasia ossificans progressiva. Dr. Yu has translated several scientific discoveries into therapeutics, including contributions to sotatercept for pulmonary arterial hypertension and the clinical repositioning of saracatinib for fibrodysplasia ossificans progressiva (FOP). He has published over 120 peer-reviewed studies and has been elected to the American Society for Clinical Investigation. Aaron Waxman, M.D., Ph.D. Dr. Aaron Waxman is Director of the Pulmonary Vascular Disease Program at Brigham and Women's Hospital and Associate Professor of Medicine at Harvard Medical School. Dr. Waxman’s clinical practice and research programs center on pulmonary arterial hypertension (PAH), right heart failure, thromboembolic disease, and the broader spectrum of pulmonary vascular disease. Across local and national efforts, Dr. Waxman has served as Principal Investigator on more than 15 clinical trials in pulmonary hypertension. These include the Phase 2 SPECTRA trial of sotatercept, which helped establish activin signaling inhibition as a novel therapeutic pathway in PAH, and the INCREASE trial of inhaled treprostinil in pulmonary hypertension associated with interstitial lung disease—a study that defined a new treatment standard for a previously underserved patient population. He has authored more than 180 peer-reviewed publications, and his research has been supported by the National Institutes of Health, including the National Heart, Lung, and Blood Institute. Steven Nathan, M.D., F.C.C.P. Dr. Steven Nathan is Schar Chair of the Advanced Lung Disease and Lung Transplant Program, Inova Health System and Professor of Education at the University of Virginia. The author of more than 500 publications and co-editor of two books on idiopathic pulmonary fibrosis, Dr. Nathan is internationally recognized for his expertise in advanced lung diseases. Dr. Nathan is a reviewer for multiple journals and is on the editorial board for the journal, Thorax. He has served on multiple committees, including U.S. Food and Drug Administration advisory boards as well as steering committees for clinical trials in IPF and pulmonary hypertension, where he has also served as chair. Dr. Nathan is the recipient of the 2023 American College of Chest Physicians’ 2023 College Medalist Award, and is a member of several professional medical associations, including the American Thoracic Society, the American College of Chest Physicians, and the International Society for Heart and Lung Transplantation. Steve Hays, M.D. Dr. Steven R. Hays is Medical Director of the UCSF Advanced Lung Disease and Lung Transplant Program and Professor of Medicine at the University of California, San Francisco. Under his leadership, the program has grown to one of the nation’s largest transplant centers while consistently achieving superior outcomes, receiving INTERLINK’s Chairman’s Award for Transplant Excellence for three consecutive years. Dr. Hays brings deep clinical expertise across the full spectrum of advanced lung disease, including cystic fibrosis, alpha-1 antitrypsin deficiency, interstitial lung disease, and emphysema. A dedicated clinical investigator, Dr. Hays has served as principal investigator on NIH-funded, industry-sponsored, and investigator-initiated trials. His research portfolio spans lung transplant immunology, chronic lung allograft dysfunction, infectious disease, and transplant digital health. He has authored more than 110 peer-reviewed publications and has been an invited speaker at the American Thoracic Society, the International Society of Heart and Lung Transplantation, and the American Society of Transplantation, among others. He is a Fellow of the American College of Chest Physicians, and a member of the American Thoracic Society and the International Society of Heart and Lung Transplantation, where he serves on the Pulmonary and Infectious Disease Councils. He is a recipient of the American Thoracic Society’s Outstanding Clinician Award and a member of the prestigious UCSF Council of Master Clinicians. Robert Baughman, M.D. Dr. Baughman is Professor Emeritus at the University of Cincinnati. Along with his longtime collaborator Dr. Elyse Lower, he has performed numerous investigator initiated trials of novel treatments for sarcoidosis, including methotrexate, thalidomide, leflunomide, infliximab, rituximab, repository corticotropin injection, pirfenidone, roflumilast, and armodafinil. For sarcoidosis associated pulmonary hypertension, he has conducted trials on bosentan, iloprost, riociguat, tadalafil, selexipag, and inhaled nitric oxide. His publications include over 350 original papers and over 70 review articles and/or book chapters. Additionally, Dr. Baughman has edited multiple books on sarcoidosis and interstitial lung disease. A recognized leader in his field, Dr. Baughman led a multi-national registry of sarcoidosis associated pulmonary hypertension (ReSAPH) and is past president of the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG). About LAM-001 LAM-001 is a proprietary, investigational, once-daily inhaled formulation of sirolimus, also known as rapamycin. LAM-001’s potential as a disease-modifying agent in pulmonary hypertension stems from its ability to inhibit mTOR-mediated pulmonary arterial smooth muscle cell proliferation. The mTOR pathway has been shown to be activated in the pulmonary arterial smooth muscle cells of patients with pulmonary hypertension, and mTOR inhibition with rapamycin has been shown to reverse smooth muscle cell hyperproliferation and attenuate pulmonary vascular remodeling and cardiopulmonary dysfunction in multiple nonclinical models. Additionally, mTOR signaling promotes fibroblast activation, myofibroblast differentiation, and extracellular matrix deposition in injured or inflamed lung tissue, and mTOR inhibition has been shown to exert direct anti-fibrotic activity, reducing collagen accumulation, suppressing profibrotic cytokine signaling, and attenuating parenchymal fibrosis. These effects are particularly relevant in PH-ILD, where vascular remodeling and progressive fibrosis evolve in parallel and amplify pulmonary vascular load. LAM-001 is designed to enhance pulmonary delivery and reduce systemic exposure, offering a promising potential disease-modifying therapy for pulmonary disease. LAM-001 is currently being studied in multiple indications including PH-ILD, a serious and progressive condition affecting an estimated ~86K patients in the U.S. and ~120K in Europe. Based on compelling Phase 2a data presented at the American Thoracic Society (ATS) in May 2026, the company is advancing LAM-001 into a Phase 2b trial in PH-ILD, with initiation planned for mid-2026 and data anticipated in the first quarter of 2028. LAM-001 is also being evaluated in a Phase 2 study in BOS, a serious complication following lung transplantation affecting an estimated ~17K patients in the U.S. and ~11K in Europe. The trial is fully enrolled, with data anticipated in the first quarter of 2027. In late 2026, the company also plans to initiate a Phase 2 study of LAM-001 in SAPH, a severe complication of sarcoidosis with no approved therapy affecting an estimated ~60K patients in the U.S. and Europe. About Quince Therapeutics, Inc. Quince Therapeutics, Inc. is committed to transforming the lives of patients facing serious, underserved diseases by developing disease-modifying therapies to treat their conditions. The company is currently developing LAM-001 for the treatment of PH-ILD, BOS, and SAPH. A Phase 2a study in PH patients has been completed, a Phase 2 clinical study in BOS patients is ongoing, a Phase 2b study in PH-ILD is anticipated to begin in mid-2026, and a Phase 2 study in SAPH is anticipated to begin in late-2026. By pioneering innovative approaches, the company aims to offer new hope and improved quality of life to patients worldwide. Forward Looking Statements Statements in this news release contain “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 as contained in Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, which are subject to the “safe harbor” created by those sections. All statements, other than statements of historical facts, may be forward-looking statements. Forward-looking statements contained in this news release may be identified by the use of words such as “believe,” “may,” “should,” “expect,” “aim,” “anticipate,” “plan,” “believe,” “estimated,” “potential,” “intend,” “will,” “can,” “seek,” or other similar words. Examples of forward-looking statements include, among others, statements relating to expectations that the SAB will be instrumental in progressing the development of LAM-001 across multiple pulmonary indications; the design and potential benefits of LAM-001, including as a disease-modifying therapy for pulmonary disease and as a treatment option that may be utilized in conjunction with currently available therapies to achieve better health outcomes; anticipated regulatory and development processes and timelines, including the expected timing to initiate the planned Phase 2b trial of LAM-001 in PH-ILD and the planned Phase 2 trial of LAM-001 in SAPH, the expected timing for data readouts from the ongoing Phase 2 trial of LAM-001 in BOS and the planned Phase 2b trial of LAM-001 in PH-ILD; the Phase 2a data of LAM-001 in PAH and PH-ILD supporting continued development of LAM-001 in PH-ILD and the potential benefit across exercise capacity, pulmonary hemodynamics, cardiac stress and lung function; observed improvements in 6MWD and PVR in the Phase 2a trial potentially suggesting broader effects on cardiopulmonary physiology; the estimated patient populations in the U.S. and Europe for PH-ILD, BOS and SAPH; and the potential advantages of mTOR inhibitors in PH-ILD. Forward-looking statements are based on Quince’s current expectations and are subject to inherent uncertainties, risks, and assumptions that are difficult to predict and could cause actual results to differ materially from what the company expects. Further, certain forward-looking statements are based on assumptions as to future events that may not prove to be accurate. Factors that could cause actual results to differ include, but are not limited to, clinical results may not be indicative of results that may be observed in the future, including in larger populations; potential safety and other complications related to LAM-001; the ability to obtain and maintain regulatory approval; competition in the company’s industry; the scope, progress and expansion of developing LAM-001; the size and growth of the market(s) therefor and the rate and degree of market acceptance thereof vis-à-vis alternative therapies; the company’s ability to attract or retain key management, members of the board of directors and other personnel; the impacts of general macroeconomic and geopolitical conditions on the company’s business and financial position; and other risks and uncertainties described in the section titled “Risk Factors” in the company’s Annual Report on Form 10-K, filed with the Securities and Exchange Commission (SEC) on April 10, 2026, and other reports as filed with the SEC. Forward-looking statements contained in this news release are made as of this date, and Quince undertakes no duty to update such information except as required under applicable law. Contacts Corey Davis, Ph.D. LifeSci Advisors, LLC cdavis@lifesciadvisors.com 212-915-2577

文献来源：Liu W, Pang PD, Wu CA, Tagle D, Wu JC. New approach methodologies for drug discovery. Cell 189, 1877–1903, April 2, 2026.通讯作者：Joseph C. Wu（斯坦福大学心血管研究所）阅读时长：约 20 分钟导读：一场历史性的范式转移药物研发是人类科学史上最艰难的挑战之一。一种候选药物从发现到上市，平均耗时逾十年、花费超过十亿美元，而最终进入临床的药物中，超过 90% 仍以失败告终。失败的两大主因——疗效不足（约 55%）与难以控制的毒性（约 28%）——共同指向同一个根本性困境：动物模型与人类生物学之间存在着无法回避的物种差异。2026 年 4 月，斯坦福大学 Joseph C. Wu 团队在《Cell》发表了一篇长达 27 页的系统性综述，首次以"新方法论"（New Approach Methodologies，NAMs）为框架，全面梳理了干细胞技术、类器官平台与人工智能三大前沿技术如何协同构建"以人为中心"的新型药物研发体系。这篇综述不仅是当前 NAMs 领域最权威、最全面的路线图文献，更预示着整个药物研发生态即将迎来的深刻重构。本文将对这篇综述进行系统性解读，力求在忠实原文的基础上，提供更丰富的背景知识与批判性视角。一、背景：为什么传统动物模型已经  难以为继 ？1.1 失败数据背后的结构性危机当前药物研发体系的核心矛盾，可以用一组数字来概括：每年全球在临床前研究上投入数千亿美元，而进入临床的药物失败率仍高达 90%。这不是偶发的技术失误，而是系统性的结构性危机。造成这一困境的主要原因包括：• 物种差异的不可克服性：啮齿类动物与人类在基因表达、代谢酶谱、免疫应答、疾病易感性等方面存在根本差异。例如，人类 CYP450 酶谱与小鼠差异显著，直接导致药物代谢预测失准；人类特有的遗传多态性（如 ALDH2 突变）在标准动物模型中根本无法体现。• 疾病模型的不完整性：复杂性疾病（如阿尔茨海默症、心力衰竭、代谢综合征）的人类临床表现无法在动物模型中完整复现。转基因动物模型只能模拟单一遗传因素，而人类疾病往往是多基因、多环境因素共同作用的结果。• 毒性评估的局限性：微生物组相关的药物毒化、特异质毒性（idiosyncratic toxicity）及遗传变异导致的个体化毒性反应，在标准动物实验中几乎无法被预测。• 伦理与效率的双重压力：动物实验耗时长、成本高，且面临日益严格的动物福利监管；同时，其对人类疾病的预测价值正受到越来越多的科学质疑。1.2 政策转向：监管体系的历史性调整值得关注的是，这场变革不仅由科学技术推动，更有强有力的政策背书。美国 FDA 与 NIH 过去二十余年间的一系列举措，正在系统性地为 NAMs 清除制度障碍： 这一政策演进轨迹清晰表明：NAMs 已从"可选项"升级为"主流方向"，而完全依赖动物模型的研发路径正在被主动、系统性地解构。二、NAMs 的技术体系：三个维度，三个递进层次综述将 NAMs 划分为三大技术支柱，三者并非相互独立，而是构成一个从分子→细胞→组织→系统的完整技术栈，并可通过组合使用（combinatorial NAMs）实现协同增效。2.1 第一支柱：2D 干细胞平台——细胞层面的人类生物学核心原理人类多能干细胞（hPSC）——包括胚胎干细胞（ESC）和诱导多能干细胞（iPSC）——具备分化为三胚层所有细胞类型的能力，可在体外生成任何人类细胞谱系。这一特性赋予了研究者"按需定制"人类细胞模型的能力，是整个 NAMs 体系的细胞学基础。iPSC 技术的革命性意义在于：它允许研究者从特定患者（包括携带特定疾病突变的患者）体细胞出发，重编程获得多能干细胞，再分化为任意目标细胞类型。这意味着每一个细胞模型都携带患者真实的基因背景，能够复现动物模型无法呈现的人类特异性疾病表型。关键技术进展（近五年）神经系统领域：• 阿尔茨海默症（AD）：iPSC 神经元成功复现 AD 晚发表型，鉴定出 neddylation 通路和 APOE4 相关机制作为治疗靶点• 帕金森病（PD）：发现 BAG956 通过促进 α-突触核蛋白聚集体的自噬清除逆转 PD 表型；光遗传学 iPSC 模型（带 optogenetic 工具）实现了对 α-突触核聚集动态过程的实时监测• 抑郁症：iPSC 衍生 GABA 中间神经元揭示了 HTR2C（5-HT2C）调控在重度抑郁中的关键作用• 额颞叶痴呆（FTD）：骨桥蛋白（osteopontin）被鉴定为神经炎症的免疫调节靶点• 进行性多发性硬化：辛伐他汀通过抑制 HMGCR 减少神经毒性，提供了新的治疗思路• ALS：轴突 TDP-43 凝聚体的清除可恢复局部翻译并修复神经肌肉接头完整性心血管领域：心血管疾病是 hPSC 模型应用最成熟、证据最丰富的领域之一，原因在于心肌细胞难以从成体组织获取，动物模型的心脏电生理特性与人类差异显著（如心率、离子通道表达）。近五年主要发现：• 吲达磺胺（indisulam）（CA12 拮抗剂）：可减轻阿霉素诱导的心脏毒性• 恩格列净（empagliflozin）：缓解肥厚型心肌病的心律失常表型• 奥美沙坦（olmesartan）：纠正 LMNA 突变心力衰竭中 ERK1 磷酸化异常• 美西律类似物：用于 LQT3 型长 QT 综合征的精准治疗• 曲喹辛（trequinsin）：限制型心肌病的潜在候选药物• 青蒿素（artesunate）：靶向 MD2 的抗心脏纤维化效应（目前无 FDA 批准药物的领域）• 塞卡替尼（saracatinib）：抑制 SRC 激酶的心脏抗纤维化作用血管与其他系统：iPSC 衍生内皮细胞、静脉内皮细胞和血管平滑肌细胞的获得，使研究者能够直接在人类细胞层面研究血管疾病：• 辛伐他汀的表观遗传调控抑制内皮-间充质转化（EndMT）• 波舒替尼（bosutinib）通过纠正 TIE2 通路逆转血管畸形表型• GSK3β 抑制改善马凡综合征的平滑肌稳定性• 恩格列净和大麻素受体 1 拮抗剂大豆苷元缓解血管炎症工具平台：报告基因系、高通量筛选与遗传修饰干细胞平台的另一重要维度是其作为"工具"的价值，而非仅仅是"模型"：• 报告基因系（Reporter Lines）：NKX2.1-GFP/MEIS2-mCherry 双报告系用于实时追踪神经元亚型分化；ABCA3-GFP 融合报告系用于儿童间质性肺病的突变特异性分析；ACTA2-RFP 肝星状细胞报告系用于肝纤维化的抗纤维化药物筛选• 高通量筛选：iPSC 衍生神经元的 miRNA 筛选鉴定 AD 和 tau 蛋白病的候选调控因子；化学发光 caspase 检测揭示内皮细胞存活相关小分子• 遗传修饰平台（Genetic Modifiers）：CRISPR 编辑 iPSC 心肌细胞分析扩张型心肌病突变；TIE2 突变静脉内皮细胞整合 DRUG-seq 进行血管畸形高通量筛选局限性与改进方向 2.2 第二支柱：3D 类器官平台——组织层面的器官仿真核心原理类器官（Organoids）是将干细胞或患者来源组织在三维空间中进行自组织培养，形成具有器官级别结构与功能的多细胞体。相比 2D 单层培养，类器官能够重现细胞间的空间关系、旁分泌信号、机械力传导以及组织级别的功能整合，是目前最接近真实人体组织的体外模型。类器官可来源于：1. hPSC 衍生类器官：通过定向分化方案生成，遗传背景均一，可大批量制备2. 患者来源类器官（PDO）：直接从患者活检组织或手术标本中建立，保留肿瘤异质性和个体特征，是精准医学的核心工具主要器官系统的研究进展脑类器官：• 脑类器官（Cerebral organoids）显示 PIKFYVE 激酶抑制剂 apilimod 可挽救额颞叶痴呆中谷氨酸诱导的毒性• 中等通量筛选鉴定 selumetinib 和 fulvestrant 作为胶质瘤侵袭抑制剂• 皮质和神经节隆起类器官揭示 APOE4 改变皮质神经发育和网络形成• 3D 打印血管扩散仿生支架支撑的中脑类器官，用于芬太尼暴露的神经活动变化建模心脏类器官：• 心脏类器官证实增殖信号抑制剂 西罗莫司（sirolimus） 在心脏移植物功能障碍中优于钙调磷酸酶抑制剂• BET 家族抑制剂（包括 FDA 批准药物 apabetalone）显示出预防新冠相关心脏损伤的潜力• 导电硅纳米线工程化心脏类器官（e-SiNWs）移植后显著改善缺血再灌注损伤大鼠的心脏收缩性能和室性重塑肝脏类器官：• 肝癌类器官的药物蛋白质基因组学分析，揭示与患者预后相关的增殖型和代谢型亚型，鉴定 temsirolimus + lenvatinib 的协同抑制效应• 工程化人肝细胞类器官结合 CRISPR 筛选，鉴定 脂肪酸去饱和酶 2（FADS2） 为肝脂肪变性的决定因子• 自组织血管化肝脏类器官移植后增强急性肝衰竭模型的存活率，并恢复代谢区带化结构肺类器官：• 肺泡类器官联合化学筛选，证明 ALK5 抑制或整合素 αVβ6 阻断可减轻肺纤维化的纤维化重塑• 肿瘤细胞衍生类器官揭示 甲福明（metformin） 与 CDK4/6 抑制剂的协同抗癌作用• 长链非编码 RNA LRTOR 被鉴定为非小细胞肺癌奥希替尼耐药的驱动因子肾脏类器官：• 集合管类器官鉴定视黄酸受体激动剂抑制常染色体显性多囊肾病的囊肿生成• 新型雷帕霉素类似物 AV457 在多囊肾病人类类器官模型中实现优于依维莫司的安全性-疗效平衡• WT1 被鉴定为肾母细胞瘤中祖细胞进展和肿瘤抑制的关键调控因子其他器官系统：• 视网膜类器官：AAV 介导的 CRX 基因增强为 CRX 视网膜病变提供基因治疗概念验证• 胃癌类器官：患者来源胃癌类器官生物库结合大规模药物筛选，为精准治疗发现提供强大资源• 胰腺癌类器官：BET 蛋白降解剂 EBET 偶联抗体 #84.7（"84-EBET"）对多种胰腺导管腺癌类器官显示强效细胞毒性精准医学应用：患者来源类器官生物库PDO 生物库是类器官平台最具临床转化价值的应用方向之一。通过整合：• 高通量药物筛选• 组织病理学分析• 基因组学与蛋白质组学图谱• 标准化疗与靶向治疗评估• CAR-T 细胞免疫治疗评估PDO 平台已在多个癌种中展示出与真实临床结局高度吻合的预测能力：• 肉瘤：优化药物选择并复现患者结局• 肝癌：鉴定可操作治疗靶点• 肺癌：前瞻性预测化疗疗效• 直肠癌：复现肿瘤组织病理学、基因改变和治疗敏感性，包括放化疗反应• 食管腺癌：重现原发肿瘤的形态、基因组和转录组特征• 胶质母细胞瘤：提供实时评估 CAR-T 细胞活性的动态测试床值得注意的是，综述还强调了患者来源肿瘤片段（PDTF）平台的补充价值——通过在体外保留完整且功能性的肿瘤微环境，PDTF 解决了常规类器官系统无法重现免疫微环境的关键局限，进一步提升了对临床免疫治疗反应的预测能力。新一代类器官工程技术生物工程方法与类器官的融合正在弥合与真实组织之间的生理学差距：• 类器官-芯片（Organoid-on-Chip）：生物工程化迷你结肠类器官芯片复现结肠细胞复杂性和功能；肾脏类器官芯片利用动态流培养实现常染色体隐性多囊肾病机制解析• 3D 生物打印：模拟血管扩散物理特性的支架支撑中脑类器官；多组分水凝胶共培养肿瘤-免疫模型评估肿瘤浸润淋巴细胞迁移和细胞毒功能• 水凝胶微胶囊：具有仿生特性的水凝胶微胶囊实现可扩展的血管化肝脏类器官生成，适合移植和肝脏再生• 运动集合体-芯片（Motor Assembloids-on-a-Chip）：人骨骼肌类器官与运动神经元球体自组织结合，复现间歇性缺氧相关呼吸障碍特征性肌肉功能障碍2.3 第三支柱：In Silico AI 平台——数据驱动的预测性药物发现核心原理AI 平台代表 NAMs 技术栈中最新的维度——通过将样本层面的实验转化为数据驱动的推断，它极大地加速了研发速度、降低了成本，同时能够处理传统方法无法企及的数据规模与复杂度。深度学习与机器学习正在重构药物发现的每一个环节，包括：• 疾病诊断与风险预测• 小分子鉴定与虚拟筛选• 临床前疗效与毒性预测• 药物重定位（Drug Repurposing）• 临床治疗选择支持治疗候选物的 AI 发现基于转录组与蛋白质组的靶点鉴定：• DLEPS（深度学习疗效预测系统）：基于化学诱导的转录组变化，预测 perillen、chikusetsusaponin IV 和 trametinib 分别对肥胖、高尿酸血症和非酒精性脂肪性肝炎的疗效• 大规模血清蛋白质组学（7,890 样本）结合机器学习，鉴定载脂蛋白、免疫相关蛋白和凝血相关蛋白与代谢综合征的相关性• 整合转录组和组织学数据的深度学习模型，鉴定 FOLR2⁺ 巨噬细胞模块作为结直肠癌治疗靶点，干预后改善化疗反应（体内验证）• iPSC 内皮细胞的 RNA-seq 机器学习分析，鉴定 XCT790（ERRα 反激动剂）作为 Notch1 相关心脏瓣膜病的候选药物（体内验证）基于临床与影像数据的药物重定位：• 利用帕金森病患者≥5 年临床进展数据，机器学习模型鉴定 二甲双胍（metformin） 作为潜在疾病修饰治疗药物• hPSC 心肌细胞的深度学习表型筛选，发现 HDAC6 抑制剂 tubastatin A 和新型抑制剂 TYA-018 对扩张型心肌病的心肌保护作用虚拟筛选与对接：• 超过 100 万化合物的虚拟筛选与对接流水线，结合迭代化学合成，鉴定 BP79（TSLPR 抑制剂）作为特应性疾病的候选药物（多器官皮肤-肺芯片验证）• 空间多模态数据集整合 AI 模型，鉴定 NAMPT 和 AREG 作为早期胃癌治疗靶点（类器官与体内验证）AI 的临床应用：诊断、预测与个性化治疗这是 AI-NAMs 独特价值所在——它能填补干细胞和类器官平台无法覆盖的临床决策支持空间。疾病诊断与风险预测： 疗效预测与治疗优化：• 患者 RNA-seq 深度学习分析用于癌症免疫治疗反应分层• 整合 CT、全切片组织病理学和临床特征的多模态模型预测头颈部鳞状细胞癌的术后放疗获益• 结合组织病理图像和基因表达谱预测膀胱癌新辅助化疗结局• 电子健康记录数据整合 AI 实现跨药物类别的抗抑郁药个性化反应预测ADMET 毒性预测：• ADMET-AI：机器学习平台，提供对候选化合物 ADMET 特性的快速准确预测，包括药物诱导心脏毒性• 图神经网络模型在清细胞肾细胞癌最大规模转录组数据集上训练，准确预测治疗反应，支持决策树模型开发下一代 AI 技术平台综述梳理了六个正在重塑 AI-NAMs 的前沿技术方向：1. 个性化医学：多组学（基因组、转录组、蛋白质组、磷酸化蛋白质组）整合工作流建立肝癌蛋白质组亚型，指导索拉非尼反应预测和个性化治疗2. 药物筛选：HCS-3DX 平台整合 AI 引导显微操作器、高灵敏多孔成像板和单细胞 AI 分析软件，在 3D 类器官模型中实现可靠的个性化医学系统3. 药物重定位：MitoReID 框架利用时间分辨线粒体成像与深度学习，以自动化、低成本的方式鉴定化合物靶点4. 药物设计：MISATO 数据集整合小分子量子力学特性与分子动力学模拟；AlphaFold 实现蛋白质结构预测革命；结构导向机器学习发现效能比现有化合物强两个数量级的 α-突触核蛋白聚集抑制剂5. 结合亲和力预测：KDBNet 深度学习算法（图神经网络）预测激酶-药物结合亲和力，改善主动学习6. 表型命中发现：利用转录组和临床多组学数据的主动深度学习框架，实现诱导复杂表型反应化合物的可扩展鉴定三、从实验台到临床床旁：NAMs 的转化成功案例3.1 干细胞衍生产品的临床转化综述汇总了多个通过 NAMs 驱动的药物已进入或正在推进临床评估：ALS（肌萎缩侧索硬化）三连发：日本团队率先将 iPSC-ALS 模型的发现推向临床：• 罗匹尼罗（Ropinirole）（UMIN000034954，日本）：I/IIa 期临床试验证明其安全性和耐受性，治疗组 ALSFRS-R 下降显著抑制，额外延长无病进展生存期 27.9 周；机制上可能通过抑制 SREBP2-胆固醇合成通路发挥作用• 波舒替尼（Bosutinib）（UMIN000036295，日本）：部分减缓 ALSFRS-R 进一步下降• 依佐加滨（Ezogabine）（NCT02450552，美国）：II 期临床证明能降低 ALS 患者皮质和脊髓运动神经元兴奋性帕金森病：MSK-DA01 的里程碑：hESC 衍生多巴胺神经元产品 MSK-DA01 在帕金森大鼠模型中恢复运动功能且无移植相关毒性或成瘤性，已完成开放标签 I 期临床试验（NCT04802733），证明安全性并支持推进到确定性临床研究。2025 年，同类产品（NCT05887466，韩国）进入 I/II 期评估。系统性硬化症：iPSC-CAR-NK 疗法：首例人体应用 hPSC 衍生 CAR-NK 疗法（靶向 CD19/BCMA）治疗重度系统性硬化症，产生显著临床改善，安全性良好——这是再生医学与免疫治疗交叉的重要里程碑。3.2 类器官进入临床• Yaq-001（NCT03202498，欧洲）：基于类器官模型评估的非吸收型肠道限制性工程碳珠吸附剂，在肝硬化临床试验中达到安全性和耐受性主要终点• NCT05317221（乳腺癌，招募中）：患者血液和乳腺癌类器官活检收集，支持全外显子组测序和类器官生物库建立• NCT06755762（癌症，招募中）：循环肿瘤细胞（CTC）衍生类器官作为评估肿瘤行为和药物反应的平台3.3 AI 药物的临床验证INS018-055：AI 时代最具代表性的成功案例（NCT05154240，新西兰）这种靶向特发性肺纤维化（IPF）的小分子完全通过 AI 驱动方法发现，从 AI 设计到进入临床试验仅历时 18 个月，安全性、耐受性和药代动力学均表现良好——展示了 AI 驱动药物研发的惊人速度潜力。2025 年，该化合物的 II 期随机临床试验（NCT05938920）在 Nature Medicine 上发表结果，进一步验证了其抗纤维化疗效。历史性里程碑：首个完全基于人类类器官疗效数据的 FDA IND 批准2025 年，FDA 批准了首个完全基于人类血管化类器官疗效数据的肿瘤新药临床试验申请（IND）——抗癌药物 BAL0891 与免疫检查点抑制剂 tislelizumab 的联合方案，无需传统动物实验数据。这是 NAMs 进入监管主流的历史性节点。四、瓶颈与挑战：理性审视 NAMs 的现实局限尽管 NAMs 展现出巨大潜力，综述对其现实局限性保持了高度的科学诚实：4.1 生物学层面的挑战• 细胞成熟度不足：大多数 iPSC 衍生细胞处于胎儿期或发育早期状态，缺乏成体细胞的代谢特征、电生理成熟度和表观遗传印记，限制了对成体疾病（尤其是老年性疾病）的建模能力• 复杂疾病表型的不完整复现：复杂疾病是多基因、多环境、多时间维度交互作用的结果，现有 NAMs 难以整合所有变量• 缺乏功能性血管化：类器官中的氧气和营养物质扩散受限，大型类器官内部存在坏死核心，影响长期培养和药物渗透均匀性• 免疫系统的缺失：大多数类器官缺乏功能性免疫细胞，限制了对免疫介导疾病和免疫治疗的建模能力4.2 技术与工程层面的挑战• 标准化和重复性：批次间变异性高，不同实验室间的可重复性仍是核心瓶颈• 扩展性：从研究规模到药物筛选所需的规模化生产，技术和成本门槛依然较高• 测量与读出方法：高维度、多参数表型的实时监测和定量分析仍有技术瓶颈• 整合复杂性：多器官、多平台系统（如 MPS）的构建需要复杂的微流控工程、材料科学和细胞生物学的深度整合4.3 AI 特有的挑战• 数据质量与偏倚：真实世界数据集常包含非结构化文本、格式不一致和人口统计学偏倚；AI 模型对分子拓扑的感知有限，可能产生错误化学结构• 稀有疾病数据稀缺：高质量训练数据对罕见病尤其不足，数据共享和隐私壁垒进一步制约进展• 计算资源与可重复性：大规模 AI 模型的训练和推断需要大量计算资源，模型可重复性仍是主动挑战• 预测结果的实验验证需求：AI 预测往往仍需生物学实验验证，形成"AI-湿实验"的迭代闭环依赖4.4 监管与转化层面的挑战• 监管认可框架尚不完整：尽管 FDA 已移除动物实验强制要求，但针对具体 NAMs 平台的验证标准、接受标准和监管指南仍在制定中• 跨平台数据整合：不一致的数据标准、非统一的检测读出和缺乏统一计算框架，限制了预测准确性• 成本与可及性：高复杂度 NAMs 平台的建立和运营成本高昂，在低资源环境中的普及面临挑战五、未来展望：乐高工厂与人类中心的药物研发管线综述用一个极具启发性的比喻来描述 NAMs 的未来愿景——乐高工厂。就像乐高积木可以组合成任何结构，每个 NAMs 组件（in silico、in vitro、in chemico）具有独特的形式和功能，可以按需组合，构建覆盖药物研发全链条的"NAMs 工具箱"：数据输入层：多组学、临床数据、影像       ↓In Silico 策略：药物设计、候选筛选、微环境设计、疾病/患者预测       ↓In Chemico 策略：ECM、生物材料、生化与机械线索（精细化分子互作和疾病建模）       ↓In Vitro 策略：类器官、类器官村庄（Organoid Villages）       ↓多尺度人类微环境优化与药物测试       ↓候选药物（疾病特异性 + 精准医学）       ↓FDA 对齐、临床转化、透明度与公众信任综述提出的组合 NAMs 管线分三步走：• Step 1：AI 基于临床数据集和疾病/患者预测，驱动微环境设计、药物设计和药物筛选• Step 2a：建立代表多样患者群体的类器官村庄（Organoid Villages）• Step 2b：结合 in chemico 化学线索和生物材料，实现针对不同疾病、不同患者的精准疾病建模（表型验证、多组学分析、功能评估）• Step 3：整合测试平台进行药物测试（疗效、安全/毒性、选择性、PK/PD、ADME、功能与结构结局），输出面向精准医学和特定疾病的候选药物动物实验的最终命运：3Rs 原则的历史性演进综述明确给出了对动物实验未来地位的预判：随着 NAMs 持续成熟，动物模型将从"核心地位"转向"支持性角色"，遵循 3Rs 原则的渐进路径：• Refinement（改良）：改进动物实验设计，减少痛苦• Reduction（减少）：通过 NAMs 减少所需动物数量• Replacement（替代）：最终以人类相关 NAMs 系统全面替代动物实验综述预判：过去 30 年，动物模型塑造了药物研发；在未来 30 年，以人为核心的 NAMs，依托多尺度平台、多组学数据与 AI 管线，将重新定义并在很大程度上取代它。六、社会与伦理维度：超越科学的思考这篇综述的难能可贵之处，在于它没有止步于科学和技术的讨论，而是专辟章节探讨 NAMs 的转化与社会维度（Box 1）。综述提出，实现 NAMs 负责任、可持续的广泛采用，需要在以下方面协同发力：跨平台整合：连接 AI 预测与细胞/类器官验证，建立一致的数据标准、统一的检测读出和计算框架监管就绪：建立标准化操作规程（SOP）、符合 FAIR 原则（可发现、可访问、可互操作、可重用）的数据共享机制，以及处理生物安全、算法可解释性和审批路径的框架制造与规模化：通过自动化和可重复工程实现临床部署所需的规模化生产公平采用：通过开放科学、跨行业合作和协调的全球指南，促进 NAMs 成为药物发现的新金标准低资源环境实施：成本效益高、模块化的 NAMs 平台，以及多语言开放获取资源库，确保广泛参与能力建设：通过 AI 辅助教育、AR/VR 实验室模拟和认证项目，培训下一代科学家、监管者和临床医生综述呼吁学术界、产业界、监管机构和患者倡导组织的全面包容性合作，以构建全球可及、以人为中心、伦理基础扎实的药物研发未来。这篇综述是理解"以人为中心的药物研发"这一历史性范式转变不可或缺的入口文献——它不仅描绘了技术的现状，更勾勒了未来三十年药物研发体系重构的完整路径图。